1. Field of the Invention
The present invention relates to fluorene compounds which are useful as protecting reagents for organic synthesis reactions. The present invention also relates to organic synthesis reactions which use such a compound and the like. More particularly, the present invention relates to fluorene compounds which are usable as protecting reagents for a C-terminal and/or a side chain of amino acid or peptide in peptide synthesis, particularly liquid phase synthesis of a peptide, and methods of peptide synthesis and organic synthesis using such a compound.
2. Discussion of the Background
Methods for the organic synthesis of compounds are generally divided largely into solid phase methods and a liquid phase methods. The solid phase method is advantageous in that isolation and purification after the reaction can be performed by filtration and washing alone. However, the solid phase method is problematic in that it essentially includes a non-homogeneous phase reaction, reaction agents and reagents need to be used in excess amounts to compensate for the low reactivity, and tracking of reaction and analysis of the reaction product on a carrier are difficult.
In an attempt to perform reactions in a homogeneous liquid phase while utilizing the advantages of the solid phase method in that isolation and purification after the reaction can be performed by filtration and washing alone, a method of isolating a particular component dissolved in a liquid as a solid has been used. This is because precipitation of a particular component alone facilitates isolation and purification after reaction.
A particular component dissolved in a solution can be precipitated only when predetermined conditions, such as chemical properties, property and relationship with solvents of the compound, are satisfied.
However, determination of precipitation conditions requires trial and error and experimental searching in most cases. In liquid phase synthesis, moreover, some compounds to be synthesized are insoluble in organic solvents used for extraction or show low solubility therein, which necessitates confirmation of the property of each compound to search for isolation and purification methods therefor. Particularly, when sequential and multistep synthesis reactions are required as in peptide synthesis and the like, since isolation and purification conditions such as precipitation, extraction and the like need to be determined based on the properties unique to the compound synthesized in each step, a long time and high cost are required.
To solve such problems, a method using a carrier molecule wherein a dissolved state and an insolubilized state (precipitated state) irreversibly change according to the varying solvent composition has been developed. Using such a carrier, an isolation target compound can be selectively precipitated from a homogeneous solution state, in other words, a particular compound can be isolated after a liquid phase reaction when other soluble components still remain in a solution, thus obviating the need to consider extraction and precipitation conditions for each compound.
However, when a polymer is used as a carrier molecule, the reaction becomes non-homogeneous due to the molecular weight distribution, as in the solid phase method, where tracking of reaction and analysis of the reaction product on a carrier are difficult to perform, since the compound is bound to a carrier.
Thus, a method using a protecting group (anchor) capable of irreversible change from a dissolved state to an insolubilized state (precipitated state) of a particular component according to the varying solvent composition has been developed. For example, JP-A-2000-44493 and Bull. Chem. Soc. Jpn., 74, 733-738 (2001) disclose methods including developing an anchor by introducing a long chain aliphatic group into a benzyl alcohol type compound (see the following structure), dissolving and reacting the anchor in a halogenated solvent, and precipitating a reacted product with methanol or acetonitrile to allow peptide chain elongation.

However, when the anchor is used for sequential reactions of peptide synthesis, deprotection of a second residue results in the production of the by-product diketopiperazine, which causes a sequence showing markedly decreased yield and peptide quality, thus posing problems in broad utility (particularly sequence containing proline). With such a benzyl type anchor, moreover, deprotection under strong acidic conditions is necessary, which prevents dissociation of a desired protecting group.
WO2007/122847 discloses a trityl type protecting group (see the following structure).
wherein m and n are each independently 0 or 1, Za is a chlorine atom or a bromine atom, and Zb is a hydroxyl group, a chlorine atom or a bromine atom.
With a protecting group of this trityl type, the formation of diketopiperazine as a by-product can be suppressed and selective deprotection can be performed. However, its property as a protecting group is too low, namely, the compound-anchor bond is easily cut and a decomposition reaction proceeds in which the anchor is dissociated even in methanol and the like. Therefore, the method is not satisfactory from the aspects of yield and quality.